Obesity, type 2 diabetes (T2DM), and insulin resistance are independent risk factors for heart failure. The long- term goal of this proposal is to understand the relationship between hyperinsulinemia and cardiac dysfunction in these populations. Hyperinsulinemia may also accelerate adverse LV remodeling in pressure overload hypertrophy and genetic reduction of insulin signaling in cardiomyocytes limits hypertrophic remodeling and reduces apoptosis in pressure overload, thereby preserving LV function. Our recent studies reveal that hyperinsulinemia desensitizes -AR-mediated stimulation of cardiac contractility by promoting 2ARGi-biased signaling and by inducing the phosphodiesterase (PDE4D), which represents a novel mechanism linking insulin resistance, hyperinsulinemia and LV dysfunction. This proposal will test the hypothesis that hyperinsulinemia attenuates LV contractility by directly impairing ?AR signaling via two distinct mechanisms: (1) Increased ?2AR/Gi coupling that inhibits adenylyl cyclase (AC) and cAMP production, and (2) Increased expression of PDE4D that increases cAMP degradation. This multi PI proposal reflects an active collaboration by the laboratories of Evan Dale Abel (University of Iowa) and Yang Kevin Xiang (University of California -Davis). Our combined expertise in myocardial insulin signaling and myocardial adrenergic signaling, using novel molecular biosensors to define subcellular adrenergic signaling domains in cardiomyocytes and a comprehensive array of mutant mouse models with perturbed IR or ?AR signaling, will address this hypothesis in the following three specific aims. Aim 1 (Xiang): Will define the molecular mechanisms for and consequences of PDE4 induction in response to chronic hyperinsulinemia. Hypothesis: Insulin signaling reduces cAMP levels by increasing cardiac PDE4 levels for cAMP hydrolysis via ?2AR-ERK dependent modulation of PDE4 transcription and protein turnover. Aim 2 (Abel): Will determine the mechanisms by which modulation of IR-??2AR signaling may attenuate obesity associated LV dysfunction. Hypothesis: Acute or chronic hyperinsulinemia will impair myocardial ?AR signaling and reduce contractility or inotropic reserve by promoting cAMP degradation and genetic or pharmacological inhibition of this crosstalk will preserve LV function in hyperinsulinemic states. Aim 3 (Abel). Will determine if IR-??2AR crosstalk contributes to LV dysfunction in heart failue or in subjects with insulin resistance. Hypothesis: LV or atrial tissue from subjects with heart failure will reveal molecular signatures consistent with increased IR-??2AR ERK activation and PDE4 induction, and insulin resistant subjects will exhibit impaired heart rate responses to sub-maximal exercise. These studies will comprehensively dissect the mechanism for IR-??AR crosstalk that limits myocardial contractility in insulin resistant states, and may lead to novel approaches for treating or preventing heart failure in the high risk population with insulin resistance and the metabolic syndrome.